The cytokine leukemia inhibitor factor (LIF) can regulate neuronal birth, survival and phenotype in cell culture. Moreover, we have found that endogenous and exogenous LIF control neurogenesis in the adult olfactory epithelium following injury in vivo. We are now using LIF knockout (KO) mice and LIF delivery by viral vectors to evaluate the hypothesis that LIF can control neurogenesis in the adult CNS in vivo. We find that viral delivery of LIF, but not LacZ, into the lateral ventricle stimulates BrdU labeling in the subventricular zone (SVZ), in the nearby hippocampus, cortex and striatum, as well as in the olfactory bulb (OB). Sacrificing animals at various times after BrdU injection shows that the labeled cells in the OB come from the SVZ, suggesting that the exogenous LIF is stimulating the production of OB granule neurons. Conversely, we find that eliciting seizure stimulates BrdU labeling in the hippocampus in wild type (WT) but not LIF knockout (KO) mice. Both of these observations will be examined further. LIF regulation of neurogenesis in the OB: (i) We will follow the fates of the BrdU + cells that migrate into the OB following injection of the LIF adenovirus into the lateral ventricle using histochemical markers. (ii) We will ask whether endogenous LIF plays a developmental role in the OB using LIF KO and WT mice and histochemical markers. (iii) To clarify interpretation of our results with LIF delivery by the adenoviral vector, we are making lentiviral vectors for comparison. LIF regulation of neurogenesis in the hippocampus: (i) We will ask if endogenous LIF controls seizure-induced neurogenesis in the hippocampus using BrdU and neuronal markers. Early results indicate many fewer BrdU+ cells in the LIF KO hippocampus than in the WT following seizure. (ii) Our experiments with lateral ventricle injection of adenoviral vectors show a remarkable stimulation of BrdU labeling in the hippocampus induced by LIF, but not LacZ. Cell-specific markers will be used to identify these proliferating cells. Analysis will be done at several stages following viral injection so as to be able to follow the fates of the cells over time.